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Model-Informed Approach Supporting Approval of Nexviazyme (Avalglucosidase Alfa-ngpt) in Pediatric Patients with Late-Onset Pompe Disease

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Abstract

In August 2021, the US Food and Drug Administration approved Nexviazyme (avalglucosidase alfa-ngpt) for intravenous infusion to treat patients 1 year of age and older with late-onset Pompe disease (LOPD). The effectiveness and safety were studied in patients with LOPD and patients with infantile-onset Pompe disease (IOPD). The dosage(s) tested in clinical trials was 20 mg/kg every other week (qow) in patients with LOPD and 20 mg/kg and 40 mg/kg qow in patients with IOPD. While patients 3 years old and greater with LOPD were eligible for participation in the pivotal trial, the youngest patient enrolled was 16 years old. Therefore, pediatric patients with LOPD were not well represented in the clinical trial. The prevalence of LOPD in pediatrics is extremely low. Thus, conducting a clinical trial in pediatric patients with LOPD would be challenging. Given the similar pathophysiology, mechanism of action, and disease manifestations across the age spectrum of patients with LOPD, the approved dosages for pediatric patients younger than 16 years old with LOPD were based on extrapolation of efficacy using a model-informed exposure bridging strategy, leveraging the safety data from pediatric patients with IOPD. Specifically, the exposure associated with 20 mg/kg qow in adult patients with LOPD was the target exposure for bridging of efficacy. The safety data obtained with 40 mg/kg qow in patients with IOPD was leveraged to support approval in pediatric patients with LOPD aged 1 year and older. This article illustrates a regulatory use of model-informed extrapolation approach for dose selection in pediatric patients with a rare disease.

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Authors and Affiliations

  1. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993, USA

    Ruo-Jing Li, Katarzyna Drozda, Jie Wang, Hao Zhu & Michael Pacanowski

  2. Createrna Science and Technology, Wuhan, China

    Lian Ma

  3. Division of Rare Diseases and Medical Genetics, Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine, Office of New Drug, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993, USA

    Ann R. Punnoose & Linda J. B. Jeng

  4. Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine, Office of New Drug, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993, USA

    Janet W. Maynard

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  1. Ruo-Jing Li
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Contributions

Acquisition, analysis, and interpretation of data for the work: Ruo-Jing Li, Lian Ma, Katarzyna Drozda, and Jie Wang. Drafting the work or revisiting it critically for important intellectual content: Ruo-Jing Li, Lian Ma, Katarzyna Drozda, Jie Wang, Ann R Punnoose, Linda J.B. Jeng, Hao Zhu, and Michael Pacanowski. Final approval of the version to be published: Michael Pacanowski, Hao Zhu, and Janet W. Maynard.

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Correspondence to Ruo-Jing Li.

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All listed authors are employees of the Food and Drug Administration of the United States. The authors report no financial interests or relationships with the commercial sponsors of any products discussed in this report.

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The views expressed in this article are those of the authors and do not necessarily reflect the official views of the FDA.

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Lian Ma’s contributions were made when she was an employee of the U.S. Food and Drug Administration.

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Li, RJ., Ma, L., Drozda, K. et al. Model-Informed Approach Supporting Approval of Nexviazyme (Avalglucosidase Alfa-ngpt) in Pediatric Patients with Late-Onset Pompe Disease. AAPS J 25, 16 (2023). https://doi.org/10.1208/s12248-023-00784-8

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